The game's setting is centered around a mansion in Rhode Island, the home of the protagonist Alexandra Roivas' grandfather and the mysterious book known as The Tome of Eternal Darkness that Alexandra finds there. The game is presented in a third-person action-adventure perspective in which the player must navigate a number of locations as twelve characters spanning different time periods. The game utilizes unique "sanity effects" to enhance the gameplay.

Initially, the player controls Alexandra as she investigates the mansion, which serves as a hub, in 2000 AD. Upon finding The Tome of Eternal Darkness, the player takes control of Pious Augustus in 26 BC. After Pious' chapter, the player resumes control of Alex as she finds additional chapter pages around the mansion. With each chapter, the player assumes control of a different character in the past, and ends with the perspective returning to Alex. Each chapter progresses the story and provides both the player and Alex the knowledge and abilities needed to progress. Alex does not actually engage in combat herself until late in the game.